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Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial.
De Castro, N, Marcy, O, Chazallon, C, Messou, E, Eholié, S, N'takpe, JB, Bhatt, N, Khosa, C, Timana Massango, I, Laureillard, D, et al
The Lancet. Infectious diseases. 2021;(6):813-822
Abstract
BACKGROUND In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz. METHODS We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765. FINDINGS Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per μL and median plasma HIV RNA concentration was 5·5 log10 copies per mL (IQR 5·0-5·8). 310 (68%) of 457 participants had bacteriologically-confirmed tuberculosis. In the intention-to-treat population, at week 48, 140 (61%) of 230 participants in the raltegravir group and 150 (66%) of 227 patients in the efavirenz had achieved virological suppression (between-group difference -5·2% [95% CI -14·0 to 3·6]), thus raltegravir did not meet the predefined criterion for non-inferiority. The most frequent adverse events were HIV-associated non-AIDS illnesses (eight [3%] of 229 patients in the raltegravir group; 21 [9%] of 230 patients in the efavirenz group) and AIDS-defining illnesses (ten [4%] patients in the raltegravir group; 13 [6%] patients in the efavirenz group). 58 (25%) of 229 patients in raltegravir group and 66 (29%) of 230 patients in the efavirenz group had grade 3 or 4 adverse events. 26 (6%) of 457 patients died during follow-up: 14 in the efavirenz group and 12 in the raltegravir group. INTERPRETATION In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients. FUNDING National French Agency for AIDS Research, Ministry of Health in Brazil, Merck. TRANSLATIONS For the Portuguese and French translations of the abstract see Supplementary Materials section.
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Immune recovery markers in a double blind clinical trial comparing dolutegravir and raltegravir based regimens as initial therapy (SPRING-2).
Blanco, JR, Alejos, B, Moreno, S
PloS one. 2020;(1):e0226724
Abstract
BACKGROUND Multiple T-cell marker recovery (MTMR: CD4+ T-cells >500 cel/mm3 plus CD4+% >29% plus CD4+/CD8+ ratio >1) has been proposed as the most complete level of immune reconstitution. In this study we quantified differences in the CD4+/CD8+ ratio, CD4+% recovery and MTMR after starting HIV-1 treatment with dolutegravir (DTG) vs. raltegravir (RAL) plus a NRTI backbone. METHODS Exploratory post-hoc analysis of the SPRING-2 study, a randomized double-blind clinical trial comparing DTG and RAL as third agents in naive HIV-infected patients at 100 sites in Canada, USA, Australia, and Europe. Percentage differences and corresponding precision based on 95% confidence intervals (CI) and p-values were calculated for i) CD4+/CD8+ ratio normalization, ii) CD4+% normalization, and iii) the achievement of MTMR. RESULTS A total of 822 participants were analyzed (411 in each group). No statistically significant differences in the proportion of patients who reached a CD4+/CD8+ ratio ≥0.5 & ≥1 at w48 & w96 were observed. At w96, the proportion of patients with a CD4+/CD8+ ratio ≥1 was similar (30.43% DTG vs. 29.57% RAL). No differences were observed in the mean increase in CD4+/CD8+ ratio from baseline at both w48 & w96. Similarly, no significant differences in the CD4+/CD8+>29% were observed at w96 (72.95% DTG vs 69.28% RAL). The proportion of patients attaining MTMR criteria was also similar in the DTG group and the RAL group at w48 (20.33% vs. 18.26%; difference 2.07 (95%CI (-3.67;7.81) P = 0.481 and w96 (28.70% vs. 27.13; difference 1.56 (95%CI -5.22;8.34) P = 0.652). CONCLUSION After comparing DTG and RAL, no differences on immune recovery markers were observed.
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Co-medications and Drug-Drug Interactions in People Living with HIV in Turkey in the Era of Integrase Inhibitors.
Yeşilbağ, Z, Şengül, Eİ, Şenoğlu, S, Aydın, ÖA, Karaosmanoğlu, HK
Current HIV research. 2020;(6):415-425
Abstract
BACKGROUND Long life expectancy in people living with human immunodeficiency virus (PLWH) caused an increase in comorbidities and co-medications. We aimed to analyse comedications and drug-drug interactions (DDIs) in antiretroviral therapy (ART)-naive PLWH in the era of integrase inhibitors. METHODS A retrospective observational study was conducted between January 2016-August 2019. Patients' characteristics and chronic co-medications were recorded. The University of Liverpool HIV drug interaction database was used for DDIs. RESULTS Among 745 patients, the chronic co-medication rate was 30.9%. Older age (p<0.001, OR:6.66, 95% CI: 3.86-11.49) and female gender (p=002, OR:2.25, 95%:1.14-4.44) were independently associated with co-medication. Cardiovascular system (CVS) and central nervous system (CNS) drugs were the most common co-medications. Older age patients (p<0.001, OR:12.04, 95% CI:4.63-36.71), having heterosexual (HS) contact (p=0.003, OR:3.8, 95% CI:1.57-9.22) were independently associated with CVS drugs use, while being men who have sex with men (MSM) (p=0.03, OR:2.59, 95% CI:1.11-6.03) were associated with CNS drugs use. DDIs were seen in 37.4% of patients with co-medications. Antidiabetics (23.3%), CNS (22.1%) and CVS drugs (19.8%) most commonly had DDIs. Contraindication was most commonly seen between inhaled corticosteroids and elvitegravir/cobicistat. A number of non-ART drugs, elvitegravir/cobicistat, antidiabetics, vitamins were independently associated with the presence of DDIs. CONCLUSION Results suggested the need for attention about co-medication in PLWH regardless of whether they are young or older. CNS drugs should be questioned more detailed in MSM, as well as CVS drugs in older HS patients. Elvitegravir/cobicistat is significantly associated with DDIs and switching to an unboosted INSTI should be considered in patients with multiple comorbidities.
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Single tablet regimen with abacavir/lamivudine/dolutegravir compared with two-drug regimen with lamivudine and dolutegravir as different strategies of simplification from a multicenter HIV cohort study.
Baldin, G, Ciccullo, A, Rusconi, S, Madeddu, G, Sterrantino, G, Freedman, A, Giacometti, A, Celani, L, Latini, A, Rossetti, B, et al
Le infezioni in medicina. 2019;(4):410-414
Abstract
We investigated the effectiveness and safety of a dual therapy (DT) with lamivudine plus dolutegravir versus a single tablet regimen (STR) with abacavir/lamivudine/dolutegravir. We performed a retrospective analysis in a cohort of virologically suppressed HIV+ patients switching to lamivudine-dolutegravir or abacavir/lamivudine/dolutegravir. We evaluated the incidence of virological failure and treatment discontinuation, as well as their predictors. Non-parametric tests were applied to assess changes in immunological and metabolic parameters. In all, 616 patients were analyzed: 380 began STR and 236 DT. In the STR group three patients experienced VF; in the DT group seven patients experienced VF. No differences in cause of treatment discontinuation were found. The estimated probability of continuing therapy at 48 weeks were 88.5 % in DT and 90.3% in STR, without a statistically significant difference (Log-rank 0.338). Regarding the metabolic profile, in the STR group there was a reduction in LDL cholesterol levels at week 48 (p=0.008), whereas in the lamivudine group there was a significant reduction in total cholesterol level at week 48 (p=0.044). Regarding the renal function, in both groups we registered a reduction in estimated glomerular filtration rate (eGFR), with a median reduction of 8.4 ml/min in the STR group (p<0.001) and 10.2 mL/min in DT (p<0.001). We found a difference in strategy option: in a context of side effect and comorbidities, dual therapy strategy was preferred. Conversely, simplification and compliance improvement more frequently translated into a DTG-STR strategy.
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Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial.
Flynn, PM, Taha, TE, Cababasay, M, Fowler, MG, Mofenson, LM, Owor, M, Fiscus, S, Stranix-Chibanda, L, Coutsoudis, A, Gnanashanmugam, D, et al
Journal of acquired immune deficiency syndromes (1999). 2018;(4):383-392
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Abstract
BACKGROUND No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING Fourteen sites in Sub-Saharan Africa and India. METHODS A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.
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Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial.
Molina, JM, Squires, K, Sax, PE, Cahn, P, Lombaard, J, DeJesus, E, Lai, MT, Xu, X, Rodgers, A, Lupinacci, L, et al
The lancet. HIV. 2018;(5):e211-e220
Abstract
BACKGROUND Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. METHODS In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than -10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. FINDINGS Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI -1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group. INTERPRETATION In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. FUNDING Merck & Co.
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Different impact of raltegravir versus efavirenz on CD4/CD8 ratio recovery in HIV-infected patients.
Serrano-Villar, S, Zhou, Y, Rodgers, AJ, Moreno, S
The Journal of antimicrobial chemotherapy. 2017;(1):235-239
Abstract
OBJECTIVES A low CD4/CD8 ratio during treated HIV identifies individuals with heightened immunoactivation and excess mortality. Whether ART regimens elicit distinct CD4/CD8 ratio recovery remains unknown. We aimed to compare the efficacy of an integrase inhibitor versus a non-nucleoside to normalize the CD4/CD8 ratio. METHODS We conducted a post hoc analysis of the STARTMRK study, a randomized, blinded, double-dummy Phase III trial of raltegravir versus efavirenz, and each in combination with tenofovir/emtricitabine, in treatment-naive HIV-infected adults. Blinding was maintained for the entire 5 year duration of the study. Kaplan-Meier methods for time-dependent variables were used to calculate the rates of CD4/CD8 normalization at different cut-offs and cumulative probabilities. Cox proportional hazard models were used to compare probabilities of CD4/CD8 normalization by treatment arm. RESULTS A total of 563 patients were analysed; 81% were males and the mean age (SD) was 37 (10) years. Raltegravir was associated with higher rates of CD4/CD8 ratio normalization at the >0.4 cut-off (median time to normalization = 56 versus 84 days; P = 0.048 by log-rank test). A Cox proportional hazard model stratified based on baseline CD4 counts showed an association between raltegravir and higher rates of CD4/CD8 ratio normalization (HR = 1.23; P = 0.02). CONCLUSIONS We herein show that normalization of the CD4/CD8 ratio above a clinically meaningful threshold may be dependent on the drug class used. Raltegravir showed faster CD4/CD8 ratio normalization compared with efavirenz, a finding with potential clinical implications. Whether other integrase inhibitors have a similar impact for this outcome remains to be explored.
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Brief Report: Randomized, Double-Blind Comparison of Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results.
Arribas, JR, Thompson, M, Sax, PE, Haas, B, McDonald, C, Wohl, DA, DeJesus, E, Clarke, AE, Guo, S, Wang, H, et al
Journal of acquired immune deficiency syndromes (1999). 2017;(2):211-218
Abstract
In 2 double-blind phase 3 trials, 1733 antiretroviral-naive adults were randomized to tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 144 weeks, TAF was superior to TDF in virologic efficacy, with 84.2% vs 80.0% having HIV-1 RNA <50 copies/mL (difference 4.2%; 95% confidence interval: 0.6% to 7.8%). TAF had less impact than TDF on bone mineral density and renal biomarkers. No participants on TAF had renal-related discontinuations vs 12 on TDF (P < 0.001), with no cases of proximal tubulopathy for TAF vs 4 for TDF. There were greater increases in lipids with TAF vs TDF, with no difference in the total cholesterol to high-density lipoprotein ratio. For initial HIV therapy, E/C/F/TAF is superior to E/C/F/TDF in efficacy and bone and renal safety.
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The effect of nutritional supplementation on quality of life in people living with HIV: a randomised controlled trial.
Tesfaye, M, Kaestel, P, Olsen, MF, Girma, T, Yilma, D, Abdissa, A, Ritz, C, Michaelsen, KF, Hanlon, C, Friis, H
Tropical medicine & international health : TM & IH. 2016;(6):735-42
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OBJECTIVE To determine the effects of lipid-based nutrient supplements (LNS) on the quality of life of people living with HIV (PLHIV) during the first 3 months of antiretroviral treatment (ART) and to investigate the effects of timing of supplementation by comparing with supplementation during the subsequent 3 months. METHODS A randomised controlled trial was conducted in three ART clinics within public health facilities in Jimma, Ethiopia. Participants were PLHIV eligible to start ART with body mass index >17 kg/m(2) and given daily supplements of 200 g of LNS containing whey or soya either during the first 3 months or the subsequent months of ART. The outcome was measured in terms of total quality-of-life scores on the adapted version of the WHOQOL-HIV-BREF assessed at baseline, three and six months. RESULTS Of the 282 participants, 186 (66.0%) were women. The mean age (SD) was 32.8 (±9.0) years, and the mean (SD) total quality-of-life score was 82.0 (±14.8) at baseline assessment. At 3 months, participants who received LNS showed better quality of life than those who only received ART without LNS (β = 6.2, 95% CI: 2.9: 9.6). At 6 months, there was no difference in total quality-of-life score between the early and delayed supplementation groups (β = 3.0, 95% CI: -0.4: 6.4). However, the early supplementation group showed higher scores on the social and spirituality domains than the delayed group. CONCLUSIONS LNS given during the first three months of ART improves the quality of life of PLHIV.
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Differential effects of sex in a West African cohort of HIV-1, HIV-2 and HIV-1/2 dually infected patients: men are worse off.
Jespersen, S, Hønge, BL, Esbjörnsson, J, Medina, C, da Silva Té, D, Correira, FG, Laursen, AL, Østergaard, L, Andersen, A, Aaby, P, et al
Tropical medicine & international health : TM & IH. 2016;(2):253-62
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OBJECTIVES Several studies have reported conflicting effects of sex on HIV-1 infection. We describe differences in baseline characteristics and assess the impact of sex on HIV progression among patients at a clinic with many HIV-2 and HIV-1/2 dually infected patients. METHODS This study utilised a retrospective cohort of treatment-naïve adults at the largest HIV clinic in Guinea-Bissau from 6 June 2005 to 1 December 2013. Baseline characteristics were assessed and the patients followed until death, transfer, loss to follow-up, or 1 June 2014. We estimated the time from the first clinic visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models. RESULTS A total of 5694 patients were included in the study, 3702 women (65%) and 1992 men (35%). Women were more likely than men to be infected with HIV-2 (19% vs. 15%, P < 0.01) or dually infected with HIV-1/2 (11% vs. 9%, P = 0.02). For all HIV types, women were younger (median 35 vs. 40 years), less likely to have schooling (55% vs. 77%) or to be married (46% vs. 67%), and had higher baseline CD4 cell counts (median 214 vs. 178 cells/μl). Men had a higher age-adjusted mortality rate (hazard rate ratio (HRR) 1.29, 95% confidence interval (CI) 1.09-1.52) and were more often lost to follow-up (HRR 1.27, 95% CI 1.17-1.39). CONCLUSION Significant differences exist between HIV-infected men and women regardless of HIV type. Men seek treatment at a later stage and, despite better socio-economic status, have higher mortality and loss to follow-up than women.